Drug Safety Evaluation in China.

PURPOSE OF REVIEW: This review aimed to introduce the regulations management and current situations of drug safety evaluation in China. RECENT FINDINGS: The nationwide implementation of good laboratory practice and good clinical practice guarantees the quality of pre-marketing drug safety evaluation. In recent years, post-marketing drug safety monitoring is changing from passive mode to the combination of active and passive monitoring. A national adverse drug reaction monitoring sentinel alliance has been created to actively identify, report, and evaluate adverse reactions, with more than 1.4 million cases reported in 2017. But the quality of the reports is not optimal, with few reports from drug manufacturers, low rate of severe reports, and trend of lag reporting. Drug safety evaluation in China is transitioning from passive monitoring to a combination mode. Drug pharmacovigilance is a powerful tool for active monitoring, but participation by drug manufacturers would be essential to an effective drug safety evaluation system.

Adverse Events to Food Supplements Containing Red Yeast Rice: Comparative Analysis of FAERS and CAERS Reporting Systems.

INTRODUCTION: Food supplements containing red yeast rice (RYR) are proposed as an alternative in statin-intolerant patients, although they actually contain natural statin(s) and their safety in clinical practice is still incompletely characterized. We described and compared adverse events (AEs) associated with RYR products submitted to reporting systems maintained by the Food and Drug Administration (FDA), with a focus on liver and muscular events. METHODS: We extracted RYR-related AEs from the FDA Adverse Event Reporting System (FAERS) [first quarter (Q1)-2004 to Q2-2016], a drug-based archive, and the Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS) (Q1-2004 to Q1-2017). Disproportionality via reporting odds ratio (ROR) with 95% confidence interval (CI) calculation and case-by-case inspection were performed, with a focus on muscular and hepatic AEs. RESULTS: One thousand three hundred AEs were extracted from FAERS (RYR mainly reported as a concomitant agent), whereas only 159 AEs were found in CAERS (RYR recorded mainly as a suspect agent). In FAERS, a large number of reports emerged for "general disorders and administration site conditions," whereas CAERS received also a high number of reports for "investigations" and "musculoskeletal and connective tissue disorders". Disproportionality analyses confirmed higher reporting of serious muscular and liver injuries: in FAERS, five cases of hepatic disorders (ROR = 13.71; 95% CI 5.44-34.57); in CAERS, 27 cases of rhabdomyolysis/myopathy (8.44; 5.44-13.10). CONCLUSIONS: Notwithstanding recognized limitations, these findings strengthen the importance of exploring multiple databases in safety assessment of RYR products, which should be monitored by clinicians for muscular and hepatic safety, and call for urgent review by policymakers to harmonize their regulatory status.

Integration of new technology into clinical practice after FDA approval.

Development of new medical technology is a crucial part of the advancement of medicine and our ability to better treat patients and their diseases. This process of development is long and arduous and requires a significant investment of human, financial and material capital. However, technology development can be rewarded richly by its impact on patient outcomes and successful sale of the product. One of the major regulatory hurdles to technology development is the Food and Drug Administration (FDA) approval process, which is necessary before a technology can be marketed and sold in the USA. Many businesses, medical providers and consumers believe that the FDA approval process is the only hurdle prior to use of the technology in day-to-day care. In order for the technology to be adopted into clinical use, reimbursement for both the device as well as the associated work performed by physicians and medical staff must be in place. Work and coverage decisions require Current Procedural Terminology (CPT) code development and Relative Value Scale Update Committee (RUC) valuation determination. Understanding these processes is crucial to the timely availability of new technology to patients and providers. Continued and better partnerships between physicians, industry, regulatory bodies and payers will facilitate bringing technology to market sooner and ensure appropriate utilization.

New technology in electrophysiology: FDA process and perspective.

The Food and Drug Administration (FDA) is a large regulatory agency that monitors everything from food, tobacco, and veterinary medicine to pharmaceutical drugs and medical devices. The Mission statement of the CDRH, one of the Centers of the FDA, in its most succinct form is to protect and promote public health. This is accomplished through timely and continued access to safe, effective, and high quality medical devices. This paper aims to review the overarching principles of the Agency's review process for cardiac devices as well as highlight some of the newer programs that FDA has engaged in to facilitate innovation, device development, research, and timely market approval.

[Core elements of safety monitoring report of medicines(Chinese patent medicines)].

Studies on post-marketing drug surveillance have become increasingly important in recent years. In particular, many researchers for traditional Chinese medicine have paid more attention to the safety of post-marketing Chinese patent medicines. Observational studies, like cohort study, registry study, and intensive hospital monitoring, were conducted to collect data on safety information. How to accurately report and assess these studies and let readers to completely understand relevant published reports and obtain transparent information about its methodology and findings remain unsolved. According to the reporting guidelines made by EQUATOR, our research team drafted a framework based on a four-year study by reference to relevant rules, guidelines and standards all over the world in the field of drug safety evaluation. Besides, we consulted relevant experts in this field and formed a framework on how to report post-marketing safety studies of Chinese patent medicines. There were seven core components, namely drug, population, setting, design, quality, adverse reaction and statistics, which could be abbreviated to DPSDQAS. We introduced the framework here to provide reference for future researchers.

Bronchial thermoplasty: Where there is smoke, there is fire.

Bronchial thermoplasty (BT) is the first nonpharmacologic interventional therapy approved by the U.S. Food and Drug Administration in 2010 for severe asthma. This approval was based on randomized sham-controlled trial called Asthma Intervention Research (AIR) 2 published in 2010. BT involves the application of radiofrequency energy to airways with an aim to selectively ablate airway smooth muscle. BT is currently marketed for patients with "severe" asthma. Most practicing clinicians apply this severity category to patients with oral corticosteroid dependence, frequent exacerbations, or a significantly reduced forced expiratory volume in 1 second along with a poor quality of life. Did the patients studied in the AIR-2 trial have these clinical features? Was there a reduction in severe asthma exacerbation achieved in the intervention group? Did any of the primary or secondary end points in the AIR-2 trial show a positive signal? There continues to be controversy regarding patient selection and primary outcome. Its efficacy in the management of the patient with difficult-to-manage asthma is uncertain. This review covered pertinent aspects of BT, the design and results of the AIR-2 trial, and provides the practicing allergist with a comprehensive overview of this therapy.

Cluster analysis of commercial samples of Bauhinia spp. using HPLC-UV/PDA and MCR-ALS/PCA without peak alignment procedure.

INTRODUCTION: Bauhinia forficata Link. is recognised by the Brazilian Health Ministry as a treatment of hypoglycemia and diabetes. Analytical methods are useful to assess the plant identity due the similarities found in plants from Bauhinia spp. HPLC-UV/PDA in combination with chemometric tools is an alternative widely used and suitable for authentication of plant material, however, the shifts of retention times for similar compounds in different samples is a problem. OBJECTIVE: To perform comparisons between the authentic medicinal plant (Bauhinia forficata Link.) and samples commercially available in drugstores claiming to be "Bauhinia spp. to treat diabetes" and to evaluate the performance of multivariate curve resolution - alternating least squares (MCR-ALS) associated to principal component analysis (PCA) when compared to pure PCA. METHODOLOGY: HPLC-UV/PDA data obtained from extracts of leaves were evaluated employing a combination of MCR-ALS and PCA, which allowed the use of the full chromatographic and spectrometric information without the need of peak alignment procedures. RESULTS: The use of MCR-ALS/PCA showed better results than the conventional PCA using only one wavelength. Only two of nine commercial samples presented characteristics similar to the authentic Bauhinia forficata spp., considering the full HPLC-UV/PDA data. CONCLUSION: The combination of MCR-ALS and PCA is very useful when applied to a group of samples where a general alignment procedure could not be applied due to the different chromatographic profiles. This work also demonstrates the need of more strict control from the health authorities regarding herbal products available on the market.

Quantitative and qualitative investigations of pharmacopoeial plant material polygoni avicularis herba by UHPLC-CAD and UHPLC-ESI-MS methods.

INTRODUCTION: Polygonum aviculare L. also known as common knotgrass is an annual herbaceous weed occurring all over the world in the temperate regions. Recent studies report that flavonol glucuronides are major constituents of common knotgrass. There is no comprehensive analytical procedure for the standardisation of Polygoni Avicularis Herba available on the European market. OBJECTIVE: To develop a method for the proper authentication and standardisation of Polygoni Avicularis Herba and to preliminary evaluate variability in qualitative and quantitative composition among commercial samples and samples from wild harvesting defined as Polygonum aviculare sensu lato. METHODOLOGY: The UHPLC-ESI(+)-MS method was used for the qualitative screening of nine independent samples of Polygonum aviculare herb. The UHPLC-CAD method was developed for the quantitation of the major compounds in an extract using quercetin-3-O-glucuronide as a standard. RESULTS: Twenty-five major constituents were detected and characterised. Among them three new natural products were tentatively identified. Twelve compounds were quantitated using a validated UHPLC-CAD method. In all nine samples flavonol glucuronides were confirmed as major compounds. The total flavonoid content was estimated for all samples and varied from 0.70 to 2.20%. CONCLUSION: The developed procedure may be used for the routine standardisation of common knotgrass. The results indicate that the pharmacopoeial approach to the authentication and standardisation of Polygonum aviculare herb should be revised.

Metamucil as an additional source of dietary fiber: impact of the quality of healthcare professionals' recommendations on users' experience.

OBJECTIVE: Metamucil® is a fiber supplementation formed by 100% natural psyllium. This study, conducted in Italy, assessed the impact of quality of pharmacists' instruction to use this product on subjects' adherence to and overall satisfaction with this test product. SUBJECTS AND METHODS: Open-label post-marketing study involving adult subjects who had purchased Metamucil® (follow-up: 14 ± 7 days). Information was collected using questionnaires dedicated to the participating subject and pharmacy. RESULTS: In total, 1480 subjects and 182 pharmacies returned their questionnaires. The mean age of the subjects was 49 years, two-thirds were female and 87% went to the pharmacy with problems related to bowel movements. The median daily dose taken over the 21-day period was 1. Adherence to the test product was associated with the quality of pharmacist's counseling (p = 0.005). Similarly, satisfaction with the tested product was associated with the quality of counseling (p < 0.001). Consumers' satisfaction was also associated with the quality of pharmacist's explanation of the benefits of the test product (p < 0.001) and with adherence (p < 0.001). 93% and 83% of subjects, respectively, stated the ease of use and their overall satisfaction with the test product, with 73% of subjects agreeing that they would continue using it. Similar findings were observed in subjects who had previously taken the most commonly used branded fiber supplements containing either partially hydrated guar gum or psyllium in the previous 6 months. 92% of pharmacists stated they would recommend Metamucil® for bowel regularity and 90% as it provides multiple benefits. CONCLUSIONS: Pharmacists' counseling is associated with consumers' adherence and satisfaction to Metamucil®. A large proportion of subjects were satisfied and would continue taking the tested product as a fiber supplement.

Biosimilars: from technical to pharmacoeconomic considerations. 30th Rencontres Nationales de Pharmacologie et Recherche clinique pour l'Innovation et l'Evaluation des Technologies de Santé. Tables rondes.

A biosimilar is a biological medicinal product claimed to be similar to a reference biological medicinal product. Its development plan includes studies comparing it with the reference product in order to confirm its similarity in terms of quality, preclinical safety, clinical efficacy, and clinical safety, including immunogenicity. Biosimilars differ from generics both in their molecular complexity and in the specific requirements that apply to them. Since patents on many biological medicinal products will expire within the next 5 years in major therapeutic areas such as oncology, rheumatology and gastroenterology and as those products are so costly to the French national health insurance system, the availability of biosimilars would have a considerable economic impact. The round table has issued a number of recommendations intended to ensure that the upcoming arrival of biosimilars on the market is a success, in which prescribing physicians would have a central role in informing and reassuring patients, an efficient monitoring of the patients treated with biologicals would be set up and time to market for biosimilars would be speeded up.

Establishment of safety evidence for Xingxue Shuxuening injection.

OBJECTIVE: To systematically investigate the safety of Xingxue Shuxuening injection (SXN) in pre- and post-marketing, and to ensure clinical drug safety. METHODS: Strict quality control in raw herb selection and production processes was adopted and pharmacology research on SXN was performed by the drug manufacturing company, Heilongjiang ZBD Pharmaceutical Co., Ltd. We systematically reviewed the safety literature of Xingxue SXN. Adverse drug reaction (ADR) data of the drug, extracted from Spontaneous Reporting System (SRS), and clinical characters based on 20 hospital information systems (HIS) in China, were analyzed. Large-scale prospective safety monitoring and Risk Minimization Action Plans (RiskMAPs) of Xingxue SXN were carried out. RESULTS: The quality of SXN was stable and controllable when it was produced. Drug toxicology studies found no effect on rabbits with hemolytic or condensed, local stimulation and muscle stimulation, and no allergic reactions in guinea pigs. The ADRs of Xingxue SXN were dizziness, phlebitis, and vomiting based on SRS data. The injection did not conform to instructions in clinical practice when we analyzed HIS database, and patient's abnormal blood urea nitrogen levels may be related to the drug, when analyzed using the propensity score method. A nested case-control study was designed and performed to analyze the influencing factors of suspected allergic reactions to SXN. The study showed that patients with an allergy history were more prone to allergic reactions (P < 0.001), and some medicine combinations could cause allergic reactions. CONCLUSION: These studies have established a body of evidence on Xingxue SXN safety, and provide a good model for Chinese medicine injection for clinical safety. The Xingxue SXN production process and toxicology research indicate the safety of the injection. However, the use of the injection is not consistent with instructed clinical practice. Xingxue SXN causes ADRs perhaps from inappropriate usage or its pharmacological action. This injection needs better RiskMAPs to ensure its clinical safety.

[Official experimental testing of biomedical products. Regulatory frame and importance of for quality, safety and efficacy]. / Staatliche experimentelle Produktprüfung von biomedizinischen Arzneimitteln. Regulatorischer Rahmen und Bedeutung für die Qualität, Sicherheit und Wirksamkeit.

The official experimental testing of biomedicinal products provides a very significant contribution to ensuring quality, safety and efficacy of these indispensable medicines. Already in the prelicensing phase or to elucidate clusters of increased adverse effects, official medicinal control laboratories are committed to perform experimental testing. The official batch release can be seen as external quality control of the manufacturer's release testing. For proficient performance in these tasks, scientific research is required, in particular on the development and refinement of test methods, and considering the continuous development of innovative biomedicinal products. This article is aimed at introducing the present thematic issue and in particular the regulatory basis of experimental product testing, and illustrates by means of several examples its great importance for the sake of the patients.

[Technical specifications for post-marketing pharmacoeconomic evaluation of Chinese medicine (draft version for comments)].

Pharmacoeconomics is an important part of the post-marketing evaluation of Chinese medicine, post-marketing pharmacoeconomic evaluation can better reflect the clinical and market value of Chinese medicine, the purpose of establishing the technical specifications for pharmacoeconomic evaluation is to make the evaluation process and results regarding Chinese patent medicines more scientific and fair. Every country's technical specifications for pharmacoeconomic evaluation act as reference guidelines, we have already drawn up the technical specifications which take into account the special characteristics of Chinese medicine; these are in preparation for post-marketing pharmacoeconomic evaluation Chinese medicine.

[Technical specifications for intensive hospital safety monitoring of post-marketing Chinese medicine (draft version for comments)].

It is of vital significance to conduct active post-marketing surveillance of Chinese medicine, as an active response to laws, rules and guidelines issued by the China food and drug administration. The standards for technological specifications based on expert consensus have been drafted. These will provide technological support in evaluating adverse drug reactions (ADRs) or adverse drug events (ADEs). The technological specifications for post-marketing surveillance focus on two surveillance designs; one is a large sample registry study to explore general population ADR/ADE characteristics, the other is a nested case-control study to explore the characteristic and mechanisms of ADRs.

[Expert consensus post-marketing evaluation scheme to detect immunotoxicity of Chinese medicine in clinical populations (draft version for comments)].

Through consensus, establish a post-marketing scheme and the technical processes to evaluate Chinese medicine's immunotoxicity on a population, as well as its beneficial influences on the immune system. Provide regulations on the collection, storage and transportation of serum samples. This article applies to the post-marketing scientific evaluation of the immunotoxicity of parenterally administered, and for other ways of taking Chinese medicine.

[Exploration of how to formulate guidelines on post-marketing traditional Chinese medicine surveillance].

Combining the world health organization's (WHO), the United States and the European union's relevant laws and guidelines on post-marketing drug surveillance to judge the status of post-marketing surveillance of traditional Chinese medicine(TCM) in China. We found that due to the late start of post-marketing surveillance of traditional Chinese medicine, the appropriate guidelines are yet to be developed. Hence, hospitals, enterprises and research institutions do not have a shared foundation from which to compare their research results. Therefore there is an urgent need to formulate such post-marketing surveillance guidelines. This paper has used as guidance various technical documents such as, "procedures to formulate national standards" and "testing methods of management in formulating traditional Chinese medicine standards" and has combined these to produce a version of post-marketing surveillance particular to Chinese medicine in China. How to formulate these guidelines is discussed and procedures and methods to formulate technical specifications are introduced. These provide a reference for future technical specifications and will assist in the development of TCM.

[Interpretation of Guidelines on Good Pharmacovigilance Practices for European Union].

Due to the limitations of pre-authorization clinical trials, the safety information obtained from them is relatively limited. Therefore, it is very necessary to carry out pharmacovigilance activities on drugs post-marketing. In order to promote the specific implementation of the new pharmacovigilance regulations, the European medicines agency (EMA) developed the Guideline on Good Pharmacovigilance Practices (GVP), as the new criteria for pharmacovigilance in the European Union (EU). Compared with the previously published, Guidelines on Pharmacovigilance for Medicinal Products for Human Use (2007), the GVP proposed more comprehensive and systematic provisions of pharmacovigilance systems, quality control systems, judgements, pharmacovigilance inspections and audits. In addition, it set more specific and comprehensive requirements on risk management systems, the management and reporting of adverse reactions to medicinal products, periodic safety update reports, post-authorization safety studies, signal management, and so on. Interpreting the basic principles, working mechanisms, key technologies and methods of the GVP provides a useful reference for us to carry out pharmacovigilance (especially regarding safety monitoring of parenterally administered Chinese medicine).

[Establishment of model of traditional Chinese medicine injections post-marketing safety monitoring].

OBJECTIVE: To establish a nurse based post-marketing safety surveillance model for traditional Chinese medicine injections (TCMIs). METHOD: A TCMIs safety monitoring team and a research hospital team engaged in the research, monitoring processes, and quality control processes were established, in order to achieve comprehensive, timely, accurate and real-time access to research data, to eliminate errors in data collection. RESULT: A triage system involving a study nurse, as the first point of contact, clinicians and clinical pharmacists was set up in a TCM hospital. Following the specified workflow involving labeling of TCM injections and using improved monitoring forms it was found that there were no missing reports at the ratio of error was zero. CONCLUSION: A research nurse as the first and main point of contact in post-marketing safety monitoring of TCM as part of a triage model, ensures that research data collected has the characteristics of authenticity, accuracy, timeliness, integrity, and eliminate errors during the process of data collection. Hospital based monitoring is a robust and operable process.

Aspectos da produção científica da vigilância sanitária de medicamentos / Aspects of scientific production on medicines sanitary surveillance

Introdução Sabe-se que a cadeia do produto farmacêutico é extensa, ampla, dinâmica e que é influenciada constantemente por diversos campos da sociedade. O estudo do risco envolvido em todo o ciclo de produtos farmacêuticos (da produção à pós-comercialização) é relevante diante das incertezas proporcionadas pela Ciência. A criação do SUS, os escândalos da falsificação de medicamentos, a consequente instauração da CPI dos medicamentos, o controle social, a implantação da Política de Medicamentos, o surgimento dos medicamentos genéricos, o advento da Anvisa e todo arcabouço legal advindo destas transformações deram força à democratização do País e a transparência da Gestão Pública. Objetivo Avaliar artigos científicos nacionais sobre aspectos da Vigilância Sanitária de Medicamentos a partir da criação do SUS (1990) até 2011. Métodos Pesquisa nas bases de dados: Lilacs, PubMed/Medline, Embase, Ipha, Web of Science e Scopus e seleção de artigos relacionados à Vigilância Sanitária de Medicamentos publicados entre 1990 e 2011. Resultados e Discussão - A esfera nacional das ações de Vigilância Sanitária foi a de maior foco de estudo (55,83 por cento ). O eixo Produção foi o mais pesquisado (50,92 por cento ) e a categoria mais estudada foi Prescrição e Dispensação (15,34 por cento ). É preocupante o reduzido número de artigos sobre Distribuição, Transporte e Armazenamento Os medicamentos de maior interesse para estudo foram os fitoterápicos (29,41 por cento ). Os autores da região Sudeste do Brasil foram os que mais publicaram (56,44 por cento ). Este fato pode estar relacionado à concentração econômica-industrial e a presença de pólos acadêmico-tecnológicos avançados nesta região geopolítica brasileira. Conclusão- A análise dos achados, opiniões e conclusões de diversos autores distribuídos pelo Brasil mostrou a ausência de qualidade, eficácia e segurança de alguns medicamentos disponíveis no mercado com inerente risco ao paciente.

[Risk control system construction of Shenfu injection].

OBJECTIVE: To ensure the stable quality of Shenfu injection, control potential risk and reduce risk damage. METHOD: To screen and evaluate the risk in the production, GAP, research and development, circulation, clinical application, intellectual property, emergency treatment,control and prevente the potential risks. RESULT: The risk-control system of Shenfu injection has been constructed initially. CONCLUSION: It has a great significance for the establishment of traditional Chinese medicive injections' risk-control system. The keys of the risk-control in future are to make strategy, perfect the organization structure and collaborating among various departments.